In univariable analysis, older age, lower serum albumin levels, lower platelet counts, higher mFIB-4, FIB-4, APRI, and eLIFT scores significantly predicted HCC development (all, P < .05; Table 3). A subsequent multivariable analysis revealed that older age (HR: 1.03; 95% CI: 1.01–1.06; P = .001) and mFIB-4 index (HR: 2.10; 95% CI: 1.09–4.02; P = .03) were independent predictors of HCC development (Table 3).
In the prediction of HCC development at 5 years, AUROCs of dynamic changes (Δ) in non-invasive tests between baseline and 3 years were assessed (n = 642). The AUROCs of ΔmFIB-4, ΔFIB-4, ΔAPRI, and ΔeLIFT scores were 0.51 (95% CI, 0.47–0.55), 0.54 (95% CI, 0.50–0.58), 0.56 (95% CI, 0.52–0.60), and 0.52 (95% CI, 0.48–0.56), respectively. The dynamic value of the mFIB-4 index did not show significantly different predictive performance as compared to that of three non-invasive tests such as ΔFIB-4, ΔAPRI, and ΔeLIFT scores (P = .19, P = .23, and P = .78, respectively). In univariable analysis for HCC development at 5 years (n = 642), dynamic change in the four non-invasive tests did not show a significant association with HCC development (Supplementary Table 2, http://links.lww.com/MD/C662).
3.3 Sensitivities of non-invasive tests based on tumor size
Sensitivities of non-invasive tests based on tumor size (<2 cm, 2–5 cm, >5 cm) in patients (n = 83) who developed HCC were analyzed. In this study, among HCC patients (n = 83), 38 patients had a tumor <2 cm in size, 34 patients had a tumor 2 to 5 cm in size, and 11 patients had a tumor >5 cm in size. The median tumor size was 2.0 cm (IQR 1.5–3.0 cm). Based on tumor size, the value of non-invasive tests tended to increase (Table 4).
Regarding sensitivities of mFIB-4 index and other tests for HCC detection based on tumor size (<2 cm, 2–5 cm, and > 5 cm), the mFIB-4 index tended to show higher sensitivities irrespective of tumor size compared with other non-invasive tests (Table 5); sensitivities in HCC patients based on tumor size were 94.7%, 76.5%, and 90.9% in tumors <2 cm, 2 to 5 cm, and >5 cm in size, respectively. Regarding predictive performance of mFIB-4 index and other tests for HCC detection based on tumors <2 cm, 2 to 5 cm, and >5 cm in size, mFIB-4 index tended to better predict HCC development in patients with a tumor ≤5 cm in size than other non-invasive tests (Table 5). Conversely, in patients with a tumor >5 cm in size, the FIB-4 index tended to better predict HCC development than other non-invasive tests.
3.4 Risk stratification for HCC development using fibrosis models
Among the four non-invasive tests, mFIB-4 showed the highest sensitivities of 92.9% (Table 2). The study population was stratified into low- and high-risk groups according to cut-off values from this study for risk prediction models (Table 6). In the stratification for the 3-year cumulative HCC incidence according to cut-off values from original studies, patients (n = 633) with a high mFIB-4 index had a significantly higher HCC risk than those (n = 291) with a low mFIB-4 index (HR: 3.14, 95% CI: 1.98–4.97, P < .001; Fig. 2B). Regarding the FIB-4 index, patients (n = 294) with a high FIB-4 index had a significantly higher HCC risk than those (n = 630) with a low FIB-4 index (HR: 1.71, 95% CI: 1.08–2.71, P = .01; Fig. 2C). Regarding APRI, patients (n = 117) with high APRI scores had a significantly higher HCC risk than those (n = 807) with low APRI scores (HR: 1.94, 95% CI: 1.01–3.73, P = .01; Fig. 2D). In stratification for HCC risk using eLIFT scores, patients (n = 541) with high eLIFT scores had a significantly higher HCC risk than those (n = 383) with low eLIFT scores (HR: 1.71, 95% CI: 1.11–2.64, P = .02; Fig. 2E).
According to mFIB-4 risk stratification that showed highest sensitivities among the four non-invasive tests, HCC developed in 24 patients who were identified among the low-risk patients (n = 291) for a median follow-up period of 62 months. Low-risk patients who developed HCC (n = 24) showed significantly lower serum platelet counts than those who did not show HCC development (n = 267; P = .01; Supplementary Table 3, http://links.lww.com/MD/C662).
This is the first study to validate newly introduced non-invasive fibrosis tests, the mFIB-4 index and the eLIFT score, with regard to the performance of predictabilities and risk stratification on HCC development in patients with compensated ALC. In this study, the mFIB-4 index showed significantly higher predictabilities for HCC development at 3 years than APRI and eLIFT scores; the mFIB-4 index significantly stratified the individual HCC risk. In a previous study, mFIB-4 index exhibited the highest diagnostic performance for cirrhosis in patients with chronic viral hepatitis B or C with an AUROC of 0.85 compared with other non-invasive tests such as APRI, FIB-4, or Lok index. Because cirrhosis is an important risk factor for HCC development and mFIB-4 index is an excellent diagnostic tool for cirrhosis of viral etiologies, good predicitive performance of mFIB-4 index for HCC development in patients with alcoholic cirrhosis can be in agreement with previous studies.
These results suggest that the mFIB-4 index can help identify ALC patients at high risk of developing HCC. When the mFIB-4 index was ≤4 points, the cumulative incidence rates of HCC at 5 years were very low (1.4%). Thus, patients with an mFIB-4 index ≤4 can be regarded as low-risk patients for HCC development. Because these low incidence rates of HCC suggest that 6-month surveillance may not be cost-effective, low-risk patients can instead be monitored less frequently at 12-month intervals. Of note, although mFIB-4 showed high sensitivities of 92.3% for HCC development at 3 years in this study, HCC developed in 0.7% of patients who were identified among low-risk patients for 3 years. Given the low-risk patients showing HCC development had low platelet counts, patients with low platelet counts may be diagnosed with HCC over long-term periods and therefore need more cautious surveillance for HCC even in low-risk patients stratified by mFIB-4. In contrast, patients with an mFIB-4 index >4 had a 4.1% cumulative incidence rate of HCC at 3 years. Thus, patients with an mFIB-4 index >4 may be regarded as high-risk patients for HCC development. These patients should be followed with caution every 6 months. Furthermore, the mFIB-4 index can be used in resource-limited settings because it does not require the use of rarely available tests for biochemical markers (such as α2-macroglobulin or apolipoprotein A1) or a costly assessment of fibrotic burden, such as transient elastography, which is not universally available. Thus, risk stratification based on the mFIB-4 index can be used widely, especially in developing countries, where the detrimental effects of alcohol are proportionally higher than in developed countries.
This study is the first to validate the eLIFT score in Asian patients with ALC, which was recently developed using a cohort of Caucasian patients with chronic liver disease. In this study, the eLIFT score was not highly accurate in predicting HCC. In a recent validation study of the eLIFT score for patients with severe hepatic fibrosis and chronic hepatitis B, the eLIFT score also showed low predictability compared to that of the FIB-4 index and APRI. Given that hepatic fibrosis is an important factor for HCC development, the low accuracy of the eLIFT score for severe hepatic fibrosis can induce low predictabilities for HCC development.
To avoid potential bias from active alcoholism when evaluating the performance of non-invasive fibrosis tests for predicting HCC development, we included patients who did not consume alcohol for at least 2 years. Although patients with active alcoholism were excluded, ongoing alcohol consumption might not affect HCC development in patients with alcoholic cirrhosis. In a recent study, multivariable analyses showed that alcohol consumption was a non-significant independent risk factor for HCC development in patients with alcoholic cirrhosis. Therefore, although we arbitrarily set “2 years” as the abstinence period to exclude patients with active alcoholism, this period may not affect the results in this study; based on a previous study, active or inactive alcoholism did not influence HCC development.
However, several limitations exist in this study. First, cirrhosis was clinically defined by gastro-endoscopic findings, blood test profiles, ultrasonographic findings, or clinical symptoms, but not by histological evaluation. However, even if a liver biopsy is available, the sensitivity and specificity of a liver biopsy are not 100%, and it can have substantial inter-observer and intra-observer variations, particularly in daily clinical practice.[25,26] The clinical approach to diagnosing cirrhosis is closer to that found in routine clinical practice. Second, fibrosis can be assessed non-invasively by Fibroscan,[27–29] which has shown potential for identifying patients at risk of HCC. Our cohort lacked Fibroscan data, so a comparison of Fibroscan with APRI and FIB-4 could not be made. Third, most patients in this study had early cirrhosis rather than advanced cirrhosis: median MELD scores were 8 and CTP scores were 5. Thus, a selection bias may exist in our results for all stages of cirrhosis, particularly advanced cirrhosis. Although our study mainly included patients with early rather than advanced cirrhosis, it may be more beneficial to prevent HCC development in the former rather than latter patients with regard to clinical aspects: early intervention may be required to prevent HCC in early cirrhotic patients. Fourth, although our study enrolled patients who did not drink alcohol as determined by a meticulous review of medical records, laboratory parameters were not available to prove abstinence in study patients. However, practical biomarkers with high sensitivity and specificity to screen ongoing alcohol consumption are not presently available. Lastly, selection bias could exist because different surveillance intervals can affect late detection of HCC development. However, in this study, the goal was not to detect the early stages of HCC, but to evaluate the performance of non-invasive fibrosis tests for predicting HCC development. Therefore, the bias might have only minimally affected the study results. Further studies are warranted to assess the performance of non-invasive fibrosis tests for predicting HCC development in patients followed up on a regular basis.
In conclusion, the mFIB-4 index, a newly developed non-invasive marker of liver fibrosis, can predict HCC and stratify HCC risk in patients with ALC. This result indicates that this index can help clinicians make surveillance strategies based on individual risk.
Conceptualization: Minjong Lee.
Data curation: Ji Hyun Kim, Minjong Lee, Seung Woo Park, Myungho Kang, Sang Hoon Lee, Tae Suk Kim, and Jin Myung Park.
Formal analysis: Ji Hyun Kim and Minjong Lee.
Funding acquisition: Minjong Lee and Dae Hee Choi.
Investigation: Ji Hyun Kim and Minjong Lee.
Methodology: Minjong Lee and Myungho Kang.
Resources: Dae Hee Choi.
Supervision: Minjong Lee.
Validation: Minjong Lee and Minjeong Kim.
Visualization: Minjong Lee and Minjeong Kim.
Writing – original draft: Minjong Lee.
Writing – review & editing: Minjong Lee and Dae Hee Choi.
Minjong Lee orcid: 0000-0002-3159-5444.
. European Association for the Study of LiverEASL-ALEH clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012;57:399–420.
. Naveau S, Raynard B, Ratziu V, et al. Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease. Clin Gastroenterol Hepatol 2005;3:167–74.
. Ho AM, Contardi LH. Pure alcoholic fatty liver and progression to cirrhosis or fibrosis. Lancet 1995;346:1562–3.
. N’Kontchou G, Paries J, Htar MT, et al. Risk factors for hepatocellular carcinoma
in patients with alcoholic or viral C cirrhosis. Clin Gastroenterol Hepatol 2006;4:1062–8.
. Masarone M, Rosato V, Dallio M, et al. Epidemiology and natural history of alcoholic liver disease. Rev Recent Clin Trials 2016;11:167–74.
. Jang JY, Kim DJ. Epidemiology of alcoholic liver disease in Korea. Clin Mol Hepatol 2018;24:93–9.
. European Association for Study of LiverEASL-ALEH clinical practice guidelines: noninvasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015;63:237–64.
. Peleg N, Sneh Arbib O, Issachar A, et al. Noninvasive scoring systems predict hepatic and extra-hepatic cancers in patients with nonalcoholic fatty liver disease. PLoS One 2018;13:e0202393.
. Peleg N, Issachar A, Sneh-Arbib O, et al. AST to Platelet Ratio Index and fibrosis 4 calculator scores for non-invasive assessment of hepatic fibrosis in patients with non-alcoholic fatty liver disease. Dig Liver Dis 2017;49:1133–8.
. Peta V, Elaribi D, Abenavoli L. Laboratory tests for diagnosis of alcoholic liver disease. Rev Recent Clin Trials 2016;11:180–4.
. Singal AK, Bataller R, Ahn J, et al. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol 2018;113:175–94.
. Wang HW, Peng CY, Lai HC, et al. New noninvasive index for predicting liver fibrosis in Asian patients with chronic viral hepatitis. Sci Rep 2017;7:3259.
. Boursier J, de Ledinghen V, Leroy V, et al. A stepwise algorithm using an at-a-glance first-line test for the non-invasive diagnosis of advanced liver fibrosis and cirrhosis. J Hepatol 2017;66:1158–65.
. Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology 2011;53:726–36.
. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–25.
. Korean Liver Cancer Study Group, National Cancer Center Korea2014 KLCSG-NCC Korea practice guideline for the management of hepatocellular carcinoma
. Gut Liver 2015;9:267–317.
. Kim DY, Kim SU, Ahn SH, et al. Usefulness of FibroScan for detection of early compensated liver cirrhosis in chronic hepatitis B. Dig Dis Sci 2009;54:1758–63.
. Jung KS, Kim SU, Ahn SH, et al. Risk assessment of hepatitis B virus-related hepatocellular carcinoma
development using liver stiffness measurement (FibroScan). Hepatology 2011;53:885–94.
. Bruix J, Sherman M. American Association for the Study of Liver DiseasesManagement of hepatocellular carcinoma
: an update. Hepatology 2011;53:1020–2.
. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837–45.
. European Association For The Study Of The Liver, European Organisation For Research and Treatment of CancerEASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma
. J Hepatol 2012;56:908–43.
. Rehm J, Mathers C, Popova S, et al. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 2009;373:2223–33.
. Li Q, Lu C, Li W, et al. Evaluation of eLIFT for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis B virus infection. Sci Rep 2017;7:5429.
. Ganne-Carrie N, Chaffaut C, Bourcier V, et al. Estimate of hepatocellular carcinoma
incidence in patients with alcoholic cirrhosis. J Hepatol 2018.
. Scheuer PJ. Liver biopsy size matters in chronic hepatitis: bigger is better. Hepatology 2003;38:1356–8.
. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495–500.
. Wong GL, Espinosa WZ, Wong VW. Personalized management of cirrhosis by non-invasive tests of liver fibrosis. Clin Mol Hepatol 2015;21:200–11.
. Jung KS, Kim SU. Clinical applications of transient elastography. Clin Mol Hepatol 2012;18:163–73.
. Castera L, Pinzani M. Non-invasive assessment of liver fibrosis: are we ready? Lancet 2010;375:1419–20.
. Kim MN, Kim SU, Kim BK, et al. Increased risk of hepatocellular carcinoma
in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis. Hepatology 2015;61:1851–9.
alcoholic liver cirrhosis; FIB-4 index; hepatocellular carcinoma; modified FIB-4 index
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